The role of glia in Huntington's disease pathology 公开
Bradford, Jennifer Webster (2010)
Published
Abstract
The role of glia in Huntington's disease pathology
By Jennifer Webster Bradford
Huntington's disease (HD) is the most common of nine inherited
polyglutamine
diseases, and is caused by an expansion of the polyglutamine tract
(>36 repeats) in the N-
terminus of the huntingtin (htt) protein. Although mutant htt is
ubiquitously expressed
throughout the body, little is known about how it impacts
non-neuronal tissues. Previous
work in our lab has demonstrated that glial cells are negatively
affected by the presence
of mutant htt, and their dysfunction could contribute to disease
progression. Glial cells
are essential components of the central nervous system, and play
crucial roles in neuronal
function and cell-cell communication, but little is known about how
mutant htt in glia
contribute to HD pathology. To this end, we generated two different
HD mouse models
that express N-terminal human mutant htt that is controlled by the
glial fibrillary acidic
protein promoter (GFAP), which drives gene expression in
astrocytes. This dissertation
describes the results from behavioral and molecular
characterization of these novel
mouse models. These studies found that expression of mutant htt in
astrocytes was
sufficient to produce a progressive, late onset HD phenotype that
included body weight
loss, decreased rotarod ability and early death, when compared with
wild type littermates
or control transgenic mice. Molecular analysis aimed at uncovering
the possible
mechanisms underlying these phenotypes revealed that the HD mice
expressing mutant
htt in astrocytes had glutamate transporter defects. It was found
that the glutamate
transporter defects were due to improper binding of mutant htt to
the Sp1 transcription
factor, which resulted in decreased gene expression. These results
challenge the classic
cell autonomous view of neurodegeneration by implying an important
role for glia in HD
pathology. These findings also suggest that treatment of astrocytes
might be a viable
target in developing new HD therapies.
Table of Contents
Table of Contents
Chapter
1:
General
Introduction
1
1.
The
polyglutamine
disease
family
2
1.1 Spinocerebellar ataxias 2
1.2 Spinobulbar muscular atrophy and dentatorubropallidoluysian
atrophy 3
1.3 Huntington's disease 4
1.4 Huntington's disease mouse models 8
2. Glial dysfunction in polyglutamine diseases
10
2.1 Types of glia in the central nervous system 11
2.2 Astrocyte glutamate transporters 12
2.3 Reactive gliosis 13
2.4 Glia and Huntington's disease 14
Chapter 2: Characterization of a novel HD mouse model that
expresses
mutant huntingtin in astrocytes
22
2.1
Abstract
23
2.2
Introduction
24
2.3
Materials
and
Methods
25
2.4
Results
28
2.5
Discussion 34
Chapter 3: Mutant huntingtin expression in mouse brain
astrocytes
results in glutamate transporter dysfunction
60
3.1
Abstract
61
3.2
Introduction
62
3.3
Materials
and
Methods
63
3.4
Results
67
3.5
Discussion 71
Chapter 4: Characterization of a BAC transgenic HD mouse model
that expresses mutant htt in astrocytes
90
4.1
Abstract
91
4.2 Introduction 92
4.3 Materials and Methods 93
4.4 Results 95
4.5 Discussion 96
Chapter 5: General conclusions and future directions 110
5.1 General Conclusions 111
5.2 Future Directions 116
References 121
About this Dissertation
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